Schizophrenia is a brain disorder that affects about 1% of the world's population and out of this number, up to a third of patients are treatment-resistant (TRS). In addition, schizophrenia is associated with suicidal ideation and 9-13% of patients eventually take their own lives. Even more troubling is the fact that 65 to 80 % of outpatients with chronic schizophrenia discontinue their antipsychotic medications, often because of a lack of efficacy or intolerable adverse effects. There is therefore an urgent need for new antipsychotics that promote compliance and ultimately treat the disease including the treatment resistant illness. The long-term goal of this proposal is to develop novel small molecules that promote ?-arrestin-2 recruitment to D2R and simultaneously interact at other CNS receptors involved in the pathophysiology of schizophrenia as new treatment options for schizophrenia. In addition, selected compounds should also not interact appreciably with receptors associated with the known side effects of current drugs. We have identified two lead compounds with this profile, SYA16263 and SYA16268 and they will form the basis of drug development to accomplish this long-term goal. The specific aims proposed to accomplish this goal, include evaluation of SYA 16263, a newly identified preclinical candidate, in a battery of tests in animal models of psychosis and to demonstrate a lack of adverse events enabling us then to move this drug or the related analog toward the clinic. Because of its newly characterized functional profile, we also plan to conduct a structure functional selectivity relationship study on SYA 16263. Specific Aim 2 will optimize the binding affinity of SYA 23013 and SYA 29875 two newly discovered agents in our labs, to D2R, 5HT1AR and 5HT7R while minimizing interactions at 5HT2BR, 5HT2CR and H1R (Ki > 500 nM). The design strategy is to obtain high potency compounds that promote b-arrestin-2 recruitment to D2R and function as antagonists (Ki<10 nM) at 5HT1AR, 5HT2AR and 5HT7R. Specific Aim 3 involves performing in vitro ADME and in vivo pharmacological evaluations of at least 1 agent per year obtained in specific aims 1 and 2 that satisfy stated physicochemical characteristics, including Lipinski's rule of five (Ro5), permeability and metabolic stability. Finally, as a faculty development grant, we also propose a specific Aim 4 which involves orchestrating a Faculty Development Strategy that will lead to obtaining non-SCORE grants. The activities include re-establishing a vibrant collaboration with experts in the field and hiring research associates/technicians to help PI deliver on the proposal aims, to establish a compound screening lab in FAMU; to write and publish ?2 articles per year and to write at least one proposal including an R21 or RO1 per year to non-SCORE funding agencies and ?2 joint RO1 proposals with collaborators.